PROJECT SUMMARY In 2019, prostate cancer will be diagnosed in an estimated 174,650 men, and account for 31,620 deaths, second only to lung cancer in terms of mortality for men. While local and regional disease typically carries an excellent prognosis, prostate cancer is a heterogeneous and diverse disease that includes both indolent and aggressive phenotypes. Androgen deprivation therapy (ADT) was the first successful treatment for men with advanced metastatic prostate cancer more than 50 years ago, and it remains a cornerstone of treatment today, but not all men will respond to ADT. The use of chemotherapy in combination with ADT significantly improved upon ADT alone in terms of overall survival. Unfortunately, despite these advances, a significant portion of men are resistance to combination chemohormonal therapy. The long-term goal of this proposal is to enable more effective treatments for men with prostate cancer. This application proposes to address this goal by investigating the mechanistic basis for chemohormonal resistance in prostate cancer using in vitro cellular studies, in vivo murine models, and retrospective patient data. Our laboratory has identified Paired-Related Homeobox Protein 2 (PRRX2) as contributing to ADT resistance in vitro. Interestingly, PRRX2 is known to promote an epithelial to mesenchymal transition (EMT), which is associated with chemoresistance in prostate cancer. However, the role of PRRX2-driven EMT has not been investigated in the context of chemohormonal resistance. Therefore, my central hypothesis is that a PRRX2- driven increase in EMT causes chemohormonal treatment resistance in prostate cancer. To test my hypothesis, with Aim 1 I will determine the contribution of PRRX2 to EMT and chemohormonal resistance using in vitro models of prostate cancer. In Aim 2, I will use in vivo mouse models determine the sufficiency of PRRX2-driven EMT for chemohormonal resistance. Finally, in Aim 3, I will evaluate the clinical relevance of my results by developing a gene signature of PRRX2-driven EMTness, and determining its association to clinical features of prostate cancer using patient data. Together, these aims will fill a fundamental gap in the understanding of prostate cancer pathogenesis, and allow for more effective treatments to be developed. I will carry out these experiments under the mentorship of my sponsor, Dr. Sarki Abdulkadir, with his extensive expertise in prostate cancer research. Dr. Abdulkadir will provide all of the necessary equipment and facilities, and access to the core facilities of Northwestern University. The training plan set out by Dr. Abdulkadir will train me as an independent researcher, while also maintaining my clinical skills to prepare me exceptionally well for the next steps of my training as a physician scientist.